PROJECT SUMMARY A detailed understanding of the transcriptional cascades involved in inner ear hair cell growth and maturation will be necessary for the development of regenerative therapies to treat hearing and vestibular disorders. It is perhaps for this reason that the National Institutes of Health (NIH) National Institute on Deafness and Other Communication Disorders (NIDCD) has set its first priority (Priority Area 1 of the 2012-2016 Strategic Plan) to understanding the mechanisms underlying normal development and function of the auditory and vestibular systems. Despite it?s known critical role in both cochlear and vestibular hair cell development and survival, no direct downstream targets of the GFI1 transcription factor have been identified in the inner ear. Moreover, specific morphological and molecular consequences of the loss of GFI1 have not yet been described. Characterizing the downstream signaling cascade of GFI1 mediated repression within developing inner ear hair cells is critical to identifying necessary factors whose expression must be controlled to reliably mimic hair cell development in vivo or in vitro. To address these gaps in knowledge, this proposal takes a three pronged approach to investigating the role of GFI1 in normal hair cell development. 1) First, the molecular and functional deficits secondary to loss of GFI1 in hair cells will be characterized. 2) Following preliminary data obtained in the sponsor?s laboratory (Ronna Hertzano, M.D., Ph.D.), the molecular mechanisms by which GFI1 promotes hair cell fate will be investigated. 3) To better understand and define key molecular pathways, comparative studies of the role of GFI1 in zebrafish hair cell development will be investigated.